EP1283053A1 - Inhibitors of HER3 activity - Google Patents

Inhibitors of HER3 activity Download PDF

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Publication number
EP1283053A1
EP1283053A1 EP01119260A EP01119260A EP1283053A1 EP 1283053 A1 EP1283053 A1 EP 1283053A1 EP 01119260 A EP01119260 A EP 01119260A EP 01119260 A EP01119260 A EP 01119260A EP 1283053 A1 EP1283053 A1 EP 1283053A1
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EP
European Patent Office
Prior art keywords
her3
antibody
composition
inhibitor
antibodies
Prior art date
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Withdrawn
Application number
EP01119260A
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German (de)
English (en)
French (fr)
Inventor
Axel Dr. Ullrich
Edward Htun-Van Der Horst
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Max Planck Gesellschaft zur Foerderung der Wissenschaften eV
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Max Planck Gesellschaft zur Foerderung der Wissenschaften eV
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Application filed by Max Planck Gesellschaft zur Foerderung der Wissenschaften eV filed Critical Max Planck Gesellschaft zur Foerderung der Wissenschaften eV
Priority to EP01119260A priority Critical patent/EP1283053A1/en
Priority to AT02794590T priority patent/ATE424219T1/de
Priority to JP2003518606A priority patent/JP5226926B2/ja
Priority to AU2002333384A priority patent/AU2002333384B2/en
Priority to PT02794590T priority patent/PT1414494E/pt
Priority to CA2456723A priority patent/CA2456723C/en
Priority to PCT/EP2002/008938 priority patent/WO2003013602A1/en
Priority to US10/486,113 priority patent/US9011851B2/en
Priority to ES02794590T priority patent/ES2323772T3/es
Priority to EP09002792A priority patent/EP2067792A2/en
Priority to CN2010105512370A priority patent/CN102078613A/zh
Priority to DE60231407T priority patent/DE60231407D1/de
Priority to EP02794590A priority patent/EP1414494B1/en
Priority to CN028156153A priority patent/CN1541109B/zh
Priority to DK02794590T priority patent/DK1414494T3/da
Publication of EP1283053A1 publication Critical patent/EP1283053A1/en
Priority to CY20091100593T priority patent/CY1110322T1/el
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/32—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
    • A61K2039/572—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 cytotoxic response
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2863—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/531—Production of immunochemical test materials
    • G01N33/532—Production of labelled immunochemicals

Definitions

  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising as an active agent an inhibitor of HER3 activity, particularly an anti-HER3-antibody. Further, the use of this composition for the diagnosis, prevention or treatment of hyperproliferative diseases, particularly tumor diseases is disclosed.
  • Protein tyrosine kinases are known to be enzymes, which mediate signal transduction processes that regulate cell growth and differentiation. Receptor protein tyrosine kinases act via ligand-stimulated tyrosine phosphorylation of substrates.
  • HER3 also called ErbB3 is a member of the epidermal growth factor receptor (EGFR) subfamily of receptor protein tyrosine kinases (Plowman et al., Proc. Natl. Acad. Sci. U.S.A. 87 (1990), 4905-4909; Kraus et al., Proc. Natl. Acad. Sci. U.S.A. 86 (1989), 9193-9197 and Kraus et al., Proc. Natl. Acad. Sci. U.S.A. 90 (1993), 2900-2904).
  • EGFR epidermal growth factor receptor
  • HER3 has been found to be overexpressed in several types of cancer such as breast, gastrointestinal and pancreatic cancers.
  • HER3 is co-expressed with HER2
  • HER2 another member of the EGFR subfamily of receptor protein tyrosine kinases, an active heterodimeric signalling complex is formed.
  • Herceptin an agonistic monoclonal antibody against HER2 with an anti-HER3-antibody ( ⁇ -HER3-ECD) (murine monoclonal antibody IgG1, Upstate Biotechnology, Cat.No.# 05-471), directed against the Heregulin binding site of HER3 in invasive breast cancer cell lines MCR-7 (DKFZ Heidelberg), MDA-MB-468 (ATCC HTB-132) and MDA-MB231 (ATCC HTB-26) expressing different HER2:HER3 ratios.
  • ⁇ -HER3-ECD murine monoclonal antibody IgG1, Upstate Biotechnology, Cat.No.# 05-471
  • ⁇ -HER3-ECD prior to ⁇ / ⁇ -Heregulin ( ⁇ / ⁇ -HRG) stimulation diminished the HER2/HER3 tyrosine phosphorylation content in contrast to Herceptin.
  • ⁇ -HER3-ECD abrogated HER2/HER3 heterodimerization and also reduced the complex formation of the p85 subunit of PI 3 -kinase and the adaptor protein SHC with HER3, resulting in decreased PI 3 -kinase and c-jun-terminal kinase activity (JNK), respectively.
  • ⁇ -HER3-ECD was also capable of downregulating extracellular signal-regulated kinase 2 (ERK2) after ⁇ / ⁇ -HRG stimulation. Furthermore, we demonstrate a significant reduction of the migratory and proliferative property of the breast cancer cell lines after pretreatment with ⁇ -HER3-ECD. These results were confirmed with murine monoclonal antibodies generated in our laboratory by immunizing Balb/c mice with the extracellular part of HER3. Our data clearly show that ⁇ -HER3-ECD is more potent in diminishing signal transduction processes after HRG stimulation than Herceptin. These data demonstrate the great potential of anti-HER3 antibodies or other inhibitory agents for the therapy of breast cancer and other malignancies characterized by hypersignalling through HER3 and its heterodimerization partners.
  • ERK2 extracellular signal-regulated kinase 2
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising as an active agent a specific type of inhibitor of HER3 activity and pharmaceutically acceptable carriers, diluents and/or adjuvants.
  • the HER3 inhibitor of the invention is characterized in that binding of the inhibitor to HER3 reduces HER3 mediated signal transduction.
  • a reduction of HER3 mediated signal transduction may be caused by a downregulation of HER3 resulting in an at least partial disappearance of HER3 molecules from the cell surface.
  • the reduction of HER3 mediated signal transduction may be caused by a stabilization of HER3 on the cell surface in a substantially inactive form, i.e. a form which exhibits a lower signal transduction compared to the non-stabilized form.
  • the inhibitor of the invention may influence the binding of Heregulin to HER3, particularly by decreasing the binding of Heregulin to HER3, it preferably does not compete with the binding of Heregulin to HER3.
  • the inhibitor is an anti-HER3-antibody.
  • the antibody is directed against the extracellular domain of HER3. It should be noted, however, that also other HER3 inhibitors, particularly low molecular weight inhibitors may be used.
  • antibody covers monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g. bispecific antibodies) formed from at least two antibodies and antibody fragments as long as they exhibit the desired activity.
  • the antibody may be a monoclonal antibody which may be obtained by the hybridoma method as described by Köhler et al. (Nature 256 (1975), 495) or by recombinant DNA methods (cf. e.g. U.S.Patent 4,816,567). Monoclonal antibodies may also be isolated from phage antibody libraries using techniques described in Clackson et al. (Nature 352 (1991), 624-628) and Marks et al. (J.Mol.Biol.222 (1991), 581-597).
  • the antibody may be an IgM, IgG, e.g. IgG1, IgG2, IgG3 or IgG4.
  • Antibody fragments comprise a portion of an antibody, generally the antigen binding or variable region of the intact antibody.
  • Examples of antibody fragments include Fab, Fab', F(ab') 2 and Fv fragments, diabodies, single chain antibody molecules and multispecific antibody fragments.
  • the antibody may be a recombinant antibody or antibody fragment, more particularly chimeric antibodies or fragments thereof (Morrison et al., Proc. Natl. Acad. Sci. U.S.A. 81 (1984), 6851-6855) or humanized antibodies (Jones et al., Nature 321 (1986), 522-525; Reichmann et al., Nature 332 (1988), 323-329 and Presta, Curr. Op. Struct. Biol. 2 (1992), 593-596) or single chain Fv antibodies (Plücktuhn in: The Pharmacology of Monoclonal Antibodies 113, Rosenburg and Moore, EDS, Springer Verlag, N.Y. (1994), pp. 269-315) and diabodies (Hollinger et al., Proc. Natl. Acad. Sci. U.S.A. 90 (1993), 6444-6448).
  • chimeric antibodies or fragments thereof or humanized antibodies
  • humanized antibodies Jone
  • the antibody is selected from antibodies 1 B4C3 (IgG2a) and 2D1 D12 (IgG1) produced by the hybridoma cell lines DSM... or DSM ACC 2517, fragments thereof or recombinant derivatives thereof.
  • 1B4C3 is an antibody which leads to internalization of HER3
  • 2D1D12 is an antibody which leads to stabilization of HER3.
  • antibodies which have substantially the same biological activity e.g. as described in the Examples
  • compared to the antibodies produced by the deposited hybridoma cell lines for example, by binding to the same epitope on HER3.
  • the hybridoma cell line DSM ACC 2517 was deposited under the Budapest Treaty for the Deposit of Microorganisms on July 24, 2001 at Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ), Mascheroder Weg 1b, 38124 Braunschweig, Germany.
  • the hybridoma cell line producing the antibody 1B4C3 was deposited on August 07, 2001 at DSMZ.
  • the antibody of the invention may be coupled to a labelling group, particularly for diagnostic applications.
  • suitable labelling groups such as radioactive groups, fluorescent groups or other labelling groups are known in the art.
  • the antibody may be coupled to an effector group, e.g. a cytotoxic group such as a radioactive group, a toxin or another effector group as known in the art.
  • the present application relates to the use of an inhibitor of HER3 activity, wherein binding of said inhibitor to HER3 reduces HER3 mediated signal transduction, for the manufacture of an agent for the diagnosis, prevention and/or treament of hyperproliferative diseases, particularly tumor diseases such as breast cancer, melanoma or tumor or formation of tumor metastasis.
  • the disease may be associated with increased HER3 signal transduction and may be associated with concomittant HER2 expression or lack of HER2 expression.
  • the disease is associated with increased HER3 phosphorylation, increased HER2/HER3 heterodimerization and/or increased PI 3 kinase and/or c-jun terminal kinase activity.
  • the HER3 inhibitor of the invention particularly an anti-HER3-antibody, shows a significantly higher efficiency in diminishing signal transduction processes than a HER2 inhibitor such as Herceptin.
  • the invention relates to a method for diangosing, preventing or treating a hyperproliferative disease, particulary a tumor disease, comprising administering a subject in need thereof, e.g. a human, an effective amount of an inhibitor of HER3 activity, wherein binding of said inhibitor to HER3 reduces HER3 mediated signal transduction.
  • the HER3 inhibitor particularly the anti-HER3-antibody may be formulated by mixing the active agent with physiologically acceptable carriers, diluents and/or adjuvants, e.g. in the form of lyophilized formulations, aqueous solutions, dispersions or solid preparations such as tablets, dragees or capsules as described in Remington's Pharmaceutical Sciences.
  • the formulation may also contain more than one active compound, e.g. inhibitors of other receptor protein tyrosine kinases such as EGFR, HER2, HER4 or vascular endothelial factor (VEGF).
  • the composition may comprise a cytotoxic agent or a cytokine.
  • the inhibitor of the invention is also suitable for diagostic applications, e.g. in order to determine the expression and/or activity of HER3 on target cells. Such a diagnostic application may be carried out according to known procedures.
  • ⁇ g/kg to 15 mg/kg of antibody may be administered to a human patient, e.g. by one or more separate administrations or by continuous infusion.
  • a typical daily dosage might range from about 1 ⁇ g/kg to about 100 mg/kg or more, depending on the factors mentioned above.
  • the treatment is sustained until a desired suppression of disease symptoms occurs.
  • Monoclonal antibody ⁇ -HER3 ECD decreases receptor tyrosine phosphorylation of HER3 and HER2
  • MCF-7 (DKFZ - Heidelberg), MDA-MB-468 (ATCC HTB-132) and MDA-MB-231 (ATCC HTB-26) were chosen on the basis of their different ratios of HER2:HER3 and their inherent migratory properties with MDA-MB-231 being the most invasive cell line.
  • HRG Heregulin
  • PY anti-phosphotyrosine antibody
  • ⁇ -HER3 ECD abrogates association of SHC and PI 3 -K with HER3 and of GRB2 with HER2
  • ⁇ -HER3 ECD has an effect on the known substrates of HER3, namely SHC and phosphatidyl-3-OH-kinase (PI 3 -K), which are effector proteins responsible for MAPK cascade activation and lipid signalling, respectively. Therefore, we immunoprecipitated SHC and PI 3 -K under the experimental conditions described above and assessed the tyrosine phosphorylation of these effectors. As shown in Figure 2, ⁇ -HER3 ECD significantly descreased the tyrosine phosphorylation of SHC in the cell lines MCF-7 and MDA-MB-486 ( Figure 2a, b compare lane 13 with 16).
  • the adaptor protein SHC mediates MAPK signalling pathways downstream of growth-factor receptors, activating ERK2 and JNK, resepectively.
  • MAPK kinase assays under the same experimental conditions in MCF-7 and MB-468 ( Figure 3).
  • ERK2 activity was only slightly but significantly decreased through ⁇ -HER3 ECD , whereas HC had no effect on ERK2 activity (data not shown).
  • ⁇ -HER3 ECD enhances endocytotic downregulation of HER3
  • HER2 and HER3 are endocytosed and recycled after HRG stimulation.
  • HER3 was then immunoprecipitated after biotinylation of the membrane proteins.
  • HER3 is endocytosed rapidly after pretreatment with ⁇ -HER3 ECD ( Figure 4b upper panel).
  • ⁇ -HER3 ECD inhibits migratory and proliferative properties of breast cancer cell lines
  • Immunization was performed by intraperitoneal injection with 22 ⁇ g of HER3-6xHis-CT according to the manufacturer's protocol (Qiagen ImmunEasy Mouse Adjuvant). Hybridoma cell lines producing monoclonal antibodies were generated using standard methods.
  • Monoclonal antibodies 1B4C3 and 2D1D12 inhibit downstream signals of HER3 and HER2
  • Monoclonal antibody 2D1D12 inhibits proliferation of breast cancer cell lines MDA-MB-435S, ZR-75-1 and melanoma cell line Mel Gerlach
  • hybridoma cell lines producing antibodies 1B4C3 and 2C1D12 were deposited on August 07, 2001 and July 24, 2001, respectively, at DSMZ.

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  • Health & Medical Sciences (AREA)
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  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
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EP01119260A 2001-08-09 2001-08-09 Inhibitors of HER3 activity Withdrawn EP1283053A1 (en)

Priority Applications (16)

Application Number Priority Date Filing Date Title
EP01119260A EP1283053A1 (en) 2001-08-09 2001-08-09 Inhibitors of HER3 activity
DK02794590T DK1414494T3 (da) 2001-08-09 2002-08-09 Hæmmende antistoffer af HER3-aktivitet
ES02794590T ES2323772T3 (es) 2001-08-09 2002-08-09 Anticuerpos inhibidores de la actividad de her3.
CN2010105512370A CN102078613A (zh) 2001-08-09 2002-08-09 Her3活性抑制剂
AU2002333384A AU2002333384B2 (en) 2001-08-09 2002-08-09 Inhibitors of HER3 activity
PT02794590T PT1414494E (pt) 2001-08-09 2002-08-09 Anticorpos inibidores da actividade de her3
CA2456723A CA2456723C (en) 2001-08-09 2002-08-09 Inhibitors of her3 activity
PCT/EP2002/008938 WO2003013602A1 (en) 2001-08-09 2002-08-09 Inhibitors of her3 activity
US10/486,113 US9011851B2 (en) 2001-08-09 2002-08-09 Inhibitors of her3 activity
AT02794590T ATE424219T1 (de) 2001-08-09 2002-08-09 Hemmende antikörper der her3-aktivität
EP09002792A EP2067792A2 (en) 2001-08-09 2002-08-09 Inhibitory antibodies of HER3 activity
JP2003518606A JP5226926B2 (ja) 2001-08-09 2002-08-09 Ｈｅｒ３活性の阻害剤
DE60231407T DE60231407D1 (de) 2001-08-09 2002-08-09 Hemmende antikörper der her3-aktivität
EP02794590A EP1414494B1 (en) 2001-08-09 2002-08-09 Inhibitory antibodies of her3 activity
CN028156153A CN1541109B (zh) 2001-08-09 2002-08-09 Her3活性抑制剂
CY20091100593T CY1110322T1 (el) 2001-08-09 2009-06-03 Αναστολεις της her3 δραστικοτητας

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Application Number Priority Date Filing Date Title
EP01119260A EP1283053A1 (en) 2001-08-09 2001-08-09 Inhibitors of HER3 activity

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EP1283053A1 true EP1283053A1 (en) 2003-02-12

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EP01119260A Withdrawn EP1283053A1 (en) 2001-08-09 2001-08-09 Inhibitors of HER3 activity
EP02794590A Revoked EP1414494B1 (en) 2001-08-09 2002-08-09 Inhibitory antibodies of her3 activity
EP09002792A Withdrawn EP2067792A2 (en) 2001-08-09 2002-08-09 Inhibitory antibodies of HER3 activity

Family Applications After (2)

Application Number Title Priority Date Filing Date
EP02794590A Revoked EP1414494B1 (en) 2001-08-09 2002-08-09 Inhibitory antibodies of her3 activity
EP09002792A Withdrawn EP2067792A2 (en) 2001-08-09 2002-08-09 Inhibitory antibodies of HER3 activity

Country Status (13)

Country Link
US (1) US9011851B2 (https=)
EP (3) EP1283053A1 (https=)
JP (1) JP5226926B2 (https=)
CN (2) CN1541109B (https=)
AT (1) ATE424219T1 (https=)
AU (1) AU2002333384B2 (https=)
CA (1) CA2456723C (https=)
CY (1) CY1110322T1 (https=)
DE (1) DE60231407D1 (https=)
DK (1) DK1414494T3 (https=)
ES (1) ES2323772T3 (https=)
PT (1) PT1414494E (https=)
WO (1) WO2003013602A1 (https=)

Cited By (8)

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WO2008100624A2 (en) 2007-02-16 2008-08-21 Merrimack Pharmaceuticals, Inc. Antibodies against erbb3 and uses thereof
EP2138511A1 (en) * 2008-06-27 2009-12-30 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. HER3 as a determinant for the prognosis of melanoma
WO2013071058A1 (en) * 2011-11-09 2013-05-16 The Uab Research Foundation Her3 antibodies and uses thereof
US8623592B2 (en) 2008-08-15 2014-01-07 Merrimack Pharmaceuticals, Inc. Methods and systems for predicting response of cells to a therapeutic agent
EP2611829A4 (en) * 2010-09-03 2014-05-07 Glaxosmithkline Ip Dev Ltd NOVEL ANTIGEN BINDING PROTEINS
US8895001B2 (en) 2010-03-11 2014-11-25 Merrimack Pharmaceuticals, Inc. Use of ErbB3 inhibitors in the treatment of triple negative and basal-like breast cancers
US9688761B2 (en) 2013-12-27 2017-06-27 Merrimack Pharmaceuticals, Inc. Biomarker profiles for predicting outcomes of cancer therapy with ERBB3 inhibitors and/or chemotherapies
US10184006B2 (en) 2015-06-04 2019-01-22 Merrimack Pharmaceuticals, Inc. Biomarkers for predicting outcomes of cancer therapy with ErbB3 inhibitors

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AUPQ105799A0 (en) 1999-06-18 1999-07-08 Victor Chang Cardiac Research Institute, The Cell growth inhibition
EP1283053A1 (en) 2001-08-09 2003-02-12 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Inhibitors of HER3 activity
AU2003218600C1 (en) * 2002-03-26 2009-12-17 Zensun (Shanghai) Science & Technology Co., Ltd. ERBB3 based methods and compositions for treating neoplasms
US8505468B2 (en) * 2002-11-19 2013-08-13 Sharp Kabushiki Kaisha Substrate accommodating tray
AR056857A1 (es) * 2005-12-30 2007-10-24 U3 Pharma Ag Anticuerpos dirigidos hacia her-3 (receptor del factor de crecimiento epidérmico humano-3) y sus usos
EP2097754B2 (en) 2006-11-28 2018-01-24 Daiichi Sankyo Europe GmbH Activated her3 as a marker for predicting therapeutic efficacy
AU2008239594B2 (en) 2007-04-13 2013-10-24 Beth Israel Deaconess Medical Center Methods for treating cancer resistant to ErbB therapeutics
PE20090321A1 (es) 2007-06-04 2009-04-20 Genentech Inc Anticuerpos anti-notch1 nrr, metodo de preparacion y composicion farmaceutica
EP2179291B1 (en) * 2007-07-13 2014-10-22 Nestec S.A. Drug selection for lung cancer therapy using antibody-based arrays
ES2637411T3 (es) 2008-12-01 2017-10-13 Laboratory Corporation Of America Holdings Métodos y ensayos para medir p95 Y/O p95 en una muestra y anticuerpos específicos para p95
EP2387711B1 (en) 2009-01-15 2015-04-22 Laboratory Corporation of America Holdings Methods of determining patient response by measurement of her-3
WO2010085845A1 (en) * 2009-01-28 2010-08-05 The University Of Queensland Cancer therapy and/or diagnosis
MY152068A (en) 2009-03-20 2014-08-15 Genentech Inc Bispecific anti-her antibodies
EP2425009A4 (en) 2009-04-29 2013-01-23 Trellis Bioscience Llc Improved antibodies immunoreactive with heregulin-coupled her3
EP2896632B1 (en) 2009-11-13 2017-10-25 Daiichi Sankyo Europe GmbH Material and methods for treating or preventing HER-3 associated diseases
RS54795B1 (sr) * 2009-12-22 2016-10-31 Roche Glycart Ag Anti-her3 antitela i njihova korišćenja
MX343227B (es) 2010-04-09 2016-10-28 Aveo Pharmaceuticals Inc Anticuerpos anti-erbb3.
PH12013500064A1 (en) 2010-07-09 2013-03-11 Exelixis Inc Combinations of kinase inhibitors for the treatment of cancer
AU2011290672B2 (en) 2010-08-20 2015-07-09 Novartis Ag Antibodies for epidermal growth factor receptor 3 (HER3)
MX347981B (es) 2010-11-01 2017-05-22 Symphogen As Composicion de anticuerpos pan-her.
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